WO2009144263A2 - Procédé d’obtention de 4-hydroxy-6-méthyl-5,6-dihydro-4h-thiéno [2,3-b] thiopyran-7,7-dioxyde et ses énantiomères, et ses applications - Google Patents

Procédé d’obtention de 4-hydroxy-6-méthyl-5,6-dihydro-4h-thiéno [2,3-b] thiopyran-7,7-dioxyde et ses énantiomères, et ses applications Download PDF

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WO2009144263A2
WO2009144263A2 PCT/EP2009/056496 EP2009056496W WO2009144263A2 WO 2009144263 A2 WO2009144263 A2 WO 2009144263A2 EP 2009056496 W EP2009056496 W EP 2009056496W WO 2009144263 A2 WO2009144263 A2 WO 2009144263A2
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thienylthio
formula
butyric acid
methyl
compound
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WO2009144263A3 (fr
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Luis Octavio Silva Guisasola
José María GORGOJO LOBATO
Luis Gerardo Gutiérrez Fuentes
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Ragactives SL
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Ragactives SL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms

Definitions

  • the invention generally relates to a process for obtaining 4-hydroxy-6-methyl-5, 6-dihydro-4H-thieno [2, 3-b] thiopyran-7, 7- dioxide and its enantiomers. Said compounds can be used as intermediates in the enantioselective synthesis of pharmaceutical active ingredients. The invention also relates to novel synthesis intermediates generated during the implementation of said process. Background of the Invention
  • Said European patent EP 296879 describes obtaining dorzolamide by means of a process in which the intermediates used are racemic compounds (enantiomer mixture) .
  • Enantiomerically pure dorzolamide requires the use of chiral resolutions in the last step of synthesis, which significantly reduces the global synthesis yield.
  • Other known synthetic processes for obtaining dorzolamide use, as precursors, intermediates which already have the suitable chirality and which allow achieving the end product in a diastereoselective form.
  • intermediates which already have the suitable chirality and which allow achieving the end product in a diastereoselective form.
  • said intermediates are the 4- hydroxy-6-alkyl-5, 6-dihydro-4H-thieno [2 , 3-b] thiopyran-7 , 7- dioxide compounds, which contain two chiral centers in carbons 4 and 6 (hereinafter, chiral hydroxysulfones) , of cis relative configuration, used as key intermediates in different syntheses.
  • Said chiral hydroxysulfones can be obtained by means of a microbiological process (US 5580764 and US 5565345) or by means of chemical synthesis.
  • United States patent US 5157129 describes a process for obtaining said chiral hydroxysulfone of cis configuration which comprises the reduction of the corresponding intermediate [5,6- dihydro-6-alkyl-4H-thieno [2, 3-b] thiopyran-4-one-7 , 7 -dioxide] with a borane derivative (e.g., diborane or a borane complex, such as borane-methyl sulfide) as a reducing agent in the presence of an oxazaborolidine .
  • a borane derivative e.g., diborane or a borane complex, such as borane-methyl sulfide
  • a process such as that provided by this invention has a number of advantages since it not only allows obtaining the desired, virtually pure cis diastereoisomer in a simple manner without having to resort to expensive purification techniques (e.g., by chromatography), but it also prevents the use of expensive reagents (e.g., the chiral catalysts used for stereoselectively performing the reduction) . This all contributes to reducing the global cost of the process, making the process of the invention an interesting process from a commercial point of view, and it allows being implemented on an industrial level .
  • the invention relates to a process for obtaining cis-4-hydroxy-6-methyl-5, 6-dihydro-4H-thieno [2, 3- b] thiopyran-7, 7-dioxide, its enantiomers or mixtures thereof, comprising the reduction of 5, 6-dihydro-6-methyl-4H-thieno [2, 3- b] thiopyran-4-one-7, 7-dioxide with a suitable reducing agent.
  • the invention relates to a process for obtaining cis-4-hydroxy-6-methyl-5, 6-dihydro-4H-thieno [2,3- b] thiopyran-7, 7-dioxide, its enantiomers or mixtures thereof, comprising (i) resolving an enantiomer mixture of 3- (2- thienylthio) butyric acid to obtain the desired enantiomer; (ii) the intramolecular cyclization of said enantiomer; (iii) the oxidation of the ketone obtained and (iv) the reduction of the 5 , 6-dihydro-6-methyl-4H-thieno [2 , 3-b] thiopyran-4-one-7 , 7-dioxide obtained with a reducing agent.
  • the invention relates to a process for obtaining the desired enantiomer of 3- (2-thienylthio) butyric acid by means of resolving an enantiomeric mixture of 3- (2- thienylthio) butyric acid using an optically active base as a resolution agent.
  • the invention relates to a process for obtaining (3S) -3- (2-thienylthio) butyric acid by means of chiral resolution of an enantiomeric mixture of 3- (2-thienylthio) butyric acid using an optically active base as a resolution agent .
  • the invention relates to a diastereoisomeric salt formed by an enantiomer of 3- (2- thienylthio) butyric acid and an optically active base selected from D- (+) - ⁇ -methylbenzylamine, 4-nitrophenyl-methylamine, L- lysine, 1- (1-naphthyl) -ethylamine (e.g., (R) -1- (1-naphthyl) - ethylamine) , 1- (2-naphthyl) -ethylamine (e.g., (R) -1- (2- naphthyl ) -ethylamine) , 1-phenylpropylamine and desoxyephedrine .
  • said diastereoisomeric salt is D- (+) -methylbenzylamine (3S) -3- (2-thienylthio) butyrate salt.
  • the invention relates to a process for the synthesis of (4S, 6S) -4- (ethylamino) -5, 6-dihydro-6-methyl-4H- thieno [2 , 3-b] thiopyran-2 -sulfonamide-7 , 7 -dioxide (dorzolamide) which comprises performing, at least one of the previously mentioned processes.
  • the invention relates to a process, hereinafter process of the invention A, for obtaining cis-4- hydroxy-6-methyl-5, 6-dihydro-4H-thieno [2, 3-b] thiopyran-7, 7- dioxide, of formula (I)
  • each asterisk (*) indicates an asymmetric carbon atom, its enantiomers or mixtures thereof, comprising the reduction of 5, 6-dihydro-6-methyl-4H-thieno [2, 3- b] thiopyran-4-one-7 , 7-dioxide of formula (II)
  • a "reducing agent which generates hydride ions” is a compound capable of transferring one or more hydride ions and which are formed or contain one or more electropositive elements selected from groups IA (alkaline metals) , I IA (alkaline earth metals) or IIIA, such as for example, lithium, sodium, potassium, aluminum, etc.; in a particular embodiment, the reducing agent which generates hydride ions has two or more different electropositive elements (e.g., lithium and aluminum, etc.); in another particular embodiment, the reducing agent which generates hydride ions further has a non-metallic element such as a non-metallic cation, for example boron (e.g., boron and lithium, boron and sodium, boron and potassium, etc.) ; and, in another particular embodiment, the reducing agent which generates hydride ions has an anion (e.g., a cyanide group (CN-
  • LiBH 4 potassium borohydride
  • KH 4 potassium borohydride
  • LiBH 4 lithium borohydride
  • LiAlH 4 lithium aluminum hydride
  • LiEtsBH lithium triethylborohydride
  • the prefix cis indicates the relative position of the substituents in the ring; specifically, said prefix cis indicates that the hydroxyl (position 4) and methyl (position 6) groups are on the same side of a common reference plane formed by the one containing the cyclic backbone.
  • the compound of formula (I) has two chiral centers, one in position 4 and the other in position 6, the absolute stereochemistry (configuration) of said chiral centers is such that the stereochemistry of the substituents in the compound of formula (I) is cis; therefore, the compound of formula (I) has 2 enantiomers:
  • Said enantiomers are intermediates useful in the synthesis of chemical compounds, including products with therapeutic applications (pharmaceutical active ingredients) ; by way of illustration, the (4R,6S)-I enantiomer can be used in the synthesis of dorzolamide.
  • a ketone of formula (II) having a methyl group in position 6 is subjected to a reduction reaction with said reducing agent which generates hydride ions, unlike what would be expected, a single enantiomer of the compound of formula (I) is substantially obtained, specifically, the enantiomer in which the hydroxyl group in position 4 is stereoselectively in cis position with regard to the methyl group present in position 6.
  • substantially means that the obtained compound of formula (I) has a cis/ trans ratio typically greater than 90%, preferably greater than 95%, and even more preferably greater than 98%.
  • the reduction of the ketone of formula (II) with said reducing agent which generates hydride ions according to the present invention allows obtaining a compound of formula (I), in which the hydroxyl group in position 4 is surprisingly, in an almost completely stereoselective manner, in cis position with regard to the methyl group in position 6.
  • the compound of formula (II) is subjected to a reduction reaction with a reducing agent which generates hydride ions, under conditions allowing the reduction of the keto group to a hydroxyl group, to obtain the compound of formula (I) .
  • said reducing agent is selected from lithium aluminum hydride (LiAlH 4 ) , lithium borohydride (LiBH 4 ) , sodium borohydride (NaBH 4 ) , potassium borohydride (KBH 4 ) , lithium super-hydride (LiEt 3 BH) and their mixtures, preferably, NaBH 4 .
  • a suitable solvent such as an organic solvent, for example, an aromatic solvent (e.g., toluene, etc.) , a halogenated solvent, such as a chlorinated hydrocarbon (e.g., methylene chloride, dichloroethane, etc.), an alcohol, such as a low molecular weight alcohol (e.g., methanol, ethanol, isopropanol, etc.), an ether, for example, an aliphatic ether (e.g., diisopropyl ether, etc.), a cyclic ether (e.g., tetrahydrofuran (THF), methyl-THF, a dioxane, etc.) , etc., at a temperature comprised between -75°C and 35°C, for a time period equal to or greater than 15 minutes, typically comprised between 30 minutes and 12 hours, which conditions allow the reduction of the keto group in position 4 to a hydroxyl group
  • a compound of formula (I) in which the hydroxyl group in position 4 is in cis with regard to the methyl group in position 6, is obtained by means of reduction of the keto group present in position 4 of the compound of formula (II) using NaBH 4 as a reducing agent and methanol as a solvent, at a reaction temperature comprised between -5°C and 20 0 C.
  • the compound of formula (II) has only one chiral center in position 6, whereas the reduced compound of formula (I) has an additional chiral center in position 4.
  • (4S,6R)-I enantiomers can be obtained.
  • the obtained compound of formula (I) is also a single enantiomer, specifically, that in which the absolute configuration of the chiral centers (positions 4 and 6) is such that the hydroxyl group in position 4 is in cis with regard to the methyl group in position 6.
  • the compound of formula (II) is a single enantiomer in which the methyl group in position 6 has (S) configuration and the obtained compound of formula (I) is the enantiomer in which the new chiral center formed in position 4 has (R) configuration and the hydroxyl group in position 4 is in cis with regard to the methyl group in position 6, specifically, the enantiomer (4R, 6S)-I.
  • (II) is a single enantiomer in which the methyl group in position 6 has (R) configuration and the obtained compound of formula (I) is the enantiomer in which the new chiral center formed in position 4 has (S) configuration and the hydroxyl group in position 4 is in cis with regard to the methyl group in position 6, specifically the (4S,6R)-I enantiomer.
  • the compound of formula (II) is an [ (R) and (S) ] enantiomer mixture and the obtained compound of formula (I) is an enantiomer mixture in which the hydroxyl group in position 4 is in cis with regard to the methyl group in position 6, specifically a (4R,6S)-I and (4S,6R)-I enantiomer mixture.
  • enantiomer mixture or “enantiomeric mixture” refers to any enantiomer mixture of a compound independently of the relative proportion between them; i.e., said mixtures can contain an excess of one of the enantiomers with regard to the other or can contain equimolecular amounts of said enantiomers, in which case they would be racemic mixtures.
  • the compound of formula (II) is selected from (6S) -5, 6-dihydro-6-methyl-4H-thieno [2, 3- b] thiopyran-4-one-7 , 7-dioxide and (6R) -5, 6-dihydro-6-methyl-4H- thieno [2 , 3-b] thiopyran-4-one-7 , 7-dioxide and the obtained compound of formula (I) is (4R, 6S) -4-hydroxy-6-methyl-5, 6- dihydro-4H-thieno [2, 3-b] thiopyran-7, 7-dioxide [ (4R, 6S) -I] or (4S, 6R) -4-hydroxy-6-methyl-5, 6-dihydro-4H-thieno [2, 3- b] thiopyran-7, 7-dioxide [ (4S, 6R) -I], respectively.
  • the invention relates to a process, hereinafter process of the invention B, for obtaining cis-4- hydroxy-6-methyl-5, 6-dihydro-4H-thieno [2, 3-b] thiopyran-7, 7- dioxide of formula (I)
  • each asterisk (*) indicates an asymmetric carbon atom, its enantiomers or mixtures thereof, comprising a) resolving an enantiomer mixture of 3- (2-thienylthio) butyric acid to obtain the desired enantiomer of formula (III) ;
  • 3- (2-thienylthio) butyric acid is a known product that has a chiral center. Obtaining 3- (2-thienylthio) butyric acid in its racemic form has been described in several documents (e.g., US 4968814, US 4968815, US 5723628 and US 5756768) .
  • the process of the invention B comprises obtaining the desired enantiomer of 3- (2-thienylthio) butyric acid by means of resolving an enantiomer mixture of said 3- (2- thienylthio) butyric acid with a suitable resolution agent, such as an optically active base.
  • Said enantiomer mixture can be a racemic mixture or a mixture enriched with any one of enantiomers.
  • the desired enantiomer of formula (III) is selected from (3S) -3- (2-thienylthio) butyric acid and (3R) -3- (2-thienylthio) butyric acid, preferably (3S) -3- (2-thienylthio) butyric acid.
  • step b) the desired enantiomer of the compound of formula (III) is subjected to an intramolecular cyclization reaction to obtain the compound of general formula (V) by conventional methods, for example, by means of any of the already previously described experimental conditions, such as the use of (CO) 2 Cl 2 /SnCl 4 (EP 296879) or by means of trifluoroacetic anhydride (EP 453288) .
  • step c) the compound of formula (II) can be obtained by means of oxidation of the sulfur in position 7 of the compound of formula (V) by conventional methods, for example, by means of the use of already described experimental conditions, for example, by means of the use of Na 2 WO 4 ZH 2 O 2 , as described in EP 453288 Al or in several publications, G. Sosnovsky et al . , Z. Naturforsch. 31b, 1376 (1976) ; and E. G. Rozantsev et al . , Synthesis, 1971, 190.
  • step d) the compound of formula (I) is obtained by subjecting the compound of formula (II) to a reduction reaction with a reducing agent which generates hydride ions, under conditions that allow the reduction of the keto group to a hydroxyl group, to obtain the compound of formula (I) .
  • a reducing agent which generates hydride ions include lithium aluminum hydride (LiAlH 4 ) , lithium borohydride (LiBH 4 ), sodium borohydride (NaBH 4 ) , potassium borohydride (KBH 4 ) , lithium super-hydride (LiEtsBH) and their mixtures, preferably NaBH 4 .
  • a suitable solvent such as an organic solvent, for example, an aromatic solvent (e.g., toluene, etc.), an halogenated solvent, such as a chlorinated hydrocarbon (e.g., methylene chloride, dichloroethane, etc.) , an alcohol, such as a low molecular weight alcohol (e.g., methanol, ethanol, isopropanol, etc.), an ether, for example, an aliphatic ether (e.g., diisopropyl ether, etc.) , a cyclic ether (e.g., tetrahydrofuran (THF) , methyl-THF, a dioxane, etc.) , etc., at a temperature comprised between -75°C and 35°C, for a time period equal to or greater than 15 minutes, typically comprised between 30 minutes and 12 hours, which conditions allow the reduction of the keto group in position 4 to a hydroxy
  • a compound of formula (I) in which the hydroxyl group in position 4 is in cis with regard to the methyl group in position 6, is obtained by means of reduction of the keto group present in position 4 of the compound of formula (II) using NaBH 4 as a reducing agent which generates hydride ions and methanol as a solvent, at a reaction temperature comprised between -5°C and 20 0 C.
  • a compound of formula (I) in which the hydroxyl group in position 4 is in cis with regard to the methyl group in position 6, is obtained by means of reduction of the keto group present in position 4 of the compound of formula (II) using LiAlH 4 as a reducing agent and THF as a solvent, at a reaction temperature comprised between - 5°C and 20 0 C.
  • step a) of the process of the invention B the resolution of the enantiomeric mixture of 3- (2-thienylthio) butyric acid to obtain the desired enantiomer of formula (III) is carried out by means of an original process and is an additional aspect of this invention.
  • the invention relates to a process for obtaining the desired enantiomer of 3- (2- thienylthio) butyric acid by means of resolving the enantiomeric mixture of 3- (2-thienylthio) butyric acid, hereinafter resolution process of the invention, comprising: a) forming diastereoisomeric salts by means of reaction of the enantiomers of said enantiomeric mixture with a resolution agent, wherein said resolution agent is an optically active base; b) recrystallizing the diastereoisomeric salts obtained in step a) in a solvent to obtain a diastereoisomeric salt enriched with the desired enantiomer; and c) obtaining the desired enantiomer by means of: c.l) resuspending the diastereoisomeric salt obtained in step b) in a suitable medium and rupture of the salt in basic medium. c.2) neutralizing the separated acid by means of its acidification until
  • the enantiomeric mixture of 3- (2-thienylthio) butyric acid can be a racemic mixture or a mixture enriched with any one of the enantiomers.
  • the desired enantiomer of 3- (2-thienylthio) butyric acid can be obtained by means of fractional crystallization of the corresponding diastereoisomeric salts formed by the reaction of enantiomers of 3- (2-thienylthio) butyric acid with a suitable resolution agent, such as an optically active base.
  • Said optically active base useful as a resolution agent can be any optically active base which forms diastereoisomeric salts with the enantiomers of 3-
  • optically active base is selected from D-(+)- ⁇ - methylbenzylamine, 4-nitrophenyl-methylamine, L-lysine, 1- (1- naphthyl) -ethylamine (e.g., (R) -1- (1-naphthyl) -ethylamine) , 1-
  • (2-naphthyl) -ethylamine e.g., (R) -1- (2-naphthyl) -ethylamine
  • 1-phenylpropylamine and desoxyephedrine preferably D-(+)- ⁇ - methylbenzylamine .
  • the diastereoisomeric salts formed by the reaction of enantiomers of 3- (2-thienylthio) butyric acid with said optically active bases are crystalline, therefore, when subjected to a crystallization process in a suitable solvent, one of said diastereoisomeric salts can be separated as a main product, and, subsequently, the desired enantiomer of 3- (2- thienylthio) butyric acid can be recovered.
  • step a) the enantiomer mixture of 3- (2- thienylthio) butyric acid comes into contact with the resolution agent (optically active base) under conditions that allow the formation of the corresponding diastereoisomeric salts, and, if desired, their isolation by conventional methods, for example, by precipitation.
  • the resolution agent optical active base
  • the reaction of enantiomers of 3- (2- thienylthio) butyric acid with the optically active base is carried out in a suitable crystallization solvent (or mixture of solvents), such as a solvent or mixture of solvents which allows completely or partially dissolving the diastereoisomeric salts and their subsequent precipitation for the purpose of obtaining the diastereoisomeric salt enriched with the desired enantiomer of 3- (2-thienylthio) butyric acid.
  • a suitable crystallization solvent or mixture of solvents
  • said crystallization solvent is an organic solvent, optionally mixed with water;
  • organic solvents that can be used as crystallization solvents include alcohols, such as low molecular weight alcohols (e.g., methanol, ethanol, isopropanol, etc.), ethers (e.g., tetrahydrofuran, methyl THF, etc.), esters (e.g., ethyl acetate, etc), ketones (e.g., acetone, etc.) , nitriles (e.g., acetonitrile, etc. ) , etc., their mixtures, or their mixtures with water.
  • said crystallization solvent is acetonitrile, optionally mixed with water.
  • the resolution agent (optically active base) can be used in a variable proportion with regard to the enantiomer mixture of 3- (2-thienylthio) butyric acid to be separated, for example, in a ratio of 0.4 to 1.5 equivalents of resolution agent to equivalent of enantiomer present in the enantiomer mixture.
  • said ratio of equivalents of resolution agent to equivalent of enantiomer present in the enantiomer mixture is from 0.5 to 0.7 equivalents.
  • step b) the diastereoisomeric salts obtained in step a) are recrystallized in a suitable solvent to obtain a diastereoisomeric salt enriched with the desired enantiomer.
  • the recrystallization of the previously obtained diastereoisomeric salts is carried out by conventional methods, for example, heating the mixture of the diastereoisomeric salts and the crystallization solvent (e.g., until boiling) and then cooling, controlling the variables of the crystallization process (e.g., cooling rate, crystallization temperature and crystallization time), which will depend on the nature of the diastereoisomeric salt to be separated and can be routinely established by a person skilled in the art; in an illustrative, non-limiting manner, the cooling rate can be comprised within a wide range, such as between 0.5°C/min and 5°C/min, for example, l°C/min, 2°C/min, 4°C/min, etc.; the crystallization temperature can vary within
  • the desired enantiomer of 3- (2-thienylthio) butyric acid can be obtained from the corresponding diastereoisomeric salt by conventional methods, for example, by means of neutralization, as mentioned in step c) .
  • a suitable solvent such as an aqueous organic medium comprising water, and at least one suitable organic solvent, such as a halogenated solvent (e.g., methylene chloride, etc.), an aromatic solvent (e.g., toluene, etc.) , an ether (e.g., THF, methyl-THF, etc.), etc.
  • a suitable solvent such as a halogenated solvent (e.g., methylene chloride, etc.), an aromatic solvent (e.g., toluene, etc.) , an ether (e.g., THF, methyl-THF, etc.), etc.
  • the pH is adjusted to a basic pH, for example between 10 and 12, to release the 3- (2-thienyl
  • any suitable strong, organic or inorganic acid can be used for said neutralization; nevertheless, in a particular embodiment, said acid is selected from the group formed by hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, etc., and their mixtures.
  • the desired enantiomer of 3- (2-thienylthio) butyric acid which normally will be in the organic phase, is isolated [step c.3)] by conventional methods, in the form of a free acid (e.g., as an oil, etc.) or in the form of a salt by means of the formation of a salt with a suitable base, for example, triethylamine, sodium hydroxide, etc.
  • the separation of the (S) enantiomer of 3- (2-thienylthio) butyric acid is performed by means of optical resolution by reacting the enantiomer mixture of 3- (2- thienylthio) butyric acid with D- (+) - ⁇ -methylbenzylamine (resolution agent) .
  • the diastereoisomeric salt containing the desired enantiomer can be recrystallized the necessary times until obtaining the desired enantiomer of 3- (2-thienylthio) butyric acid, e.g., (3S) -3- (2-thienylthio) butyric acid, with the desired purity.
  • Said diastereoisomeric salts obtained by reaction of enantiomers of 3- (2-thienylthio) butyric acid and said resolution agent, as well as their crystallization and release to obtain the desired enantiomer of 3- (2-thienylthio) butyric acid [compound of formula (III) ] have not been previously described and involve an advantageous method for obtaining said enantiomers of formula (III) with the desired stereochemistry and are an additional aspect of the present invention.
  • said diastereoisomeric salt is selected from D- (+) -methylbenzylamine (3S) -3- (2-thienylthio) butyrate salt and D- (+) -methylbenzylamine (3R) -3- (2-thienylthio) butyrate salt.
  • the invention provides a process for obtaining (3S) -3- (2-thienylthio) butyric acid by means of the chiral resolution of an enantiomeric mixture of 3- (2-thienylthio) butyric acid, using an optically active base as a resolution agent, in a medium comprising an organic solvent or an aqueous organic mixture as a solvent, in which the diastereoisomeric salts formed are subjected to one or more recrystallizations followed by isolation and recovery of the desired enantiomer [ (3S) -3- (2-thienylthio) butyric acid] by rupture of the diastereoisomeric salt by means of basification in aqueous organic medium, phase separation and subsequent neutralization (acidulation) of the aqueous phase in the presence of an organic phase with an acid medium and subsequent phase separation.
  • the compound of formula (I) can be used as an intermediate in the synthesis of dorzolamide [ (4S, 6S) -4- (ethylamino) -5, 6- dihydro-6-methyl-4H-thieno [2 , 3-b] thiopyran- 2 -sulfonamide-7 , 7- dioxide] by means of conventional methods, for example, by means of the transformation of said compound of formula (I), particularly of the compound (4R, 6S)-I, into the corresponding trans [ (4S, 6S) -4- (ethylamino) -5, 6-dihydro-6-methyl-4H- thieno [2 , 3-b] thiopyran-7 , 7-dioxide] ethylamine by means of the conversion of the hydroxyl group into a leaving group and subsequent bimolecular nucleophilic substitution with ethylamine, as described in US 5157129, and subsequent introduction of the sulfonamide group in position 2 of the thiophene
  • said transformation can be performed using as a nucleophile an azide anion that is subsequently transformed into the ethylamino group (US 5319772) .
  • said transformation of the hydroxyl group in position 4 of the compound (I) into the corresponding ethylamino group in trans with regard to the methyl group in position 6 is performed by means of a Mitsunobu reaction with inversion of the configuration (EP 1813618) and subsequent introduction of the sulfonamide group in position 2 of the thiophene ring.
  • the introduction of said sulfonamide group in said position can be performed by directly reacting said compound (4S, 6S) -4- (ethylamino) -5, 6-dihydro-6-methyl-4H- thieno [2 , 3-b] thiopyran-7 , 7-dioxide with fuming sulfuric acid (US 5157129) , or prior protection of the amino group by means of the formation of an amide and subsequent addition of chlorosulfonic acid, chlorination of the resulting intermediate by means of the addition of thionyl chloride, and the formation of the sulfonamide by the addition of aqueous ammonia (US 7030250) .
  • an additional aspect of this invention is the use of one of the processes of the invention (A or B) in the synthesis of dorzolamide, as well as a process for the synthesis of dorzolamide comprising the use of
  • (3S) -3- (2-thienylthio) butyric acid obtained by resolving 3- (2- thienylthio) butyric acid with an optically active base e.g., D- (+) -methylbenzylamine, 4-nitrophenyl-methylamine, L-lysine, 1- ( 1-naphthyl) -ethylamine (e.g., (R) -1- (2-naphthyl) -ethylamine) , 1- (2-naphthyl) -ethylamine (e.g., (R)-I- (2-naphthyl ) -ethylamine) , 1-phenylpropylamine or desoxyephedrine) as a resolution agent, or the use of the diastereoisomeric salts formed by reaction of 3- (2-thienylthio) butyric acid with said optically active base, as has been previously described.
  • the process for obtaining dorzolamide comprises a reduction step for reducing the compound 5, 6-dihydro-6-methyl-4H-thieno [2 , 3-b] thiopyran-4-one-7, 7 -dioxide with a reducing agent which generates hydride ions to obtain the intermediate cis-4-hydroxy-6-methyl-5, 6-dihydro-4H-thieno [2,3- b] thiopyran-7, 7-dioxide, its enantiomers or mixtures thereof (process of the invention A) .
  • the process for obtaining dorzolamide comprises performing the steps of: (i) resolution of an enantiomer mixture of 3- (2-thienylthio) butyric acid to obtain the desired enantiomer; (ii) intramolecular cyclization of said enantiomer; (iii) oxidation of the obtained ketone; and (iv) reduction of the 5, 6-dihydro-6-methyl-4H-thieno [2, 3- b] thiopyran-4-one-7, 7-dioxide obtained with a reducing agent which generates hydride ions, to obtain the compound cis-4- hydroxy-6-methyl-5 , 6-dihydro-4H-thieno [2, 3-b] thiopyran-7, 7- dioxide, its enantiomers or mixtures thereof (process of the invention B) .
  • the following examples illustrate the invention and must not be considered as limiting of the scope of the same.
  • the enantiomeric excess is measured by means of the transformation of (3S) -3- (2-thienylthio) butyric acid into a diastereoisomeric salt mixture by HPLC (High Performance Liquid Chromatography) ; these salts are obtained by means of dissolving the obtained oil in toluene by adding D- (+) -methylbenzylamine and EEDQ (N-ethoxycarbonyl-2-ethoxy-l, 2-dihydroquinoline) , heating to reflux, cooling, distilling the toluene and dissolving in acetonitrile .
  • the enantiomeric excess is 99%.
  • the organic phase was concentrated until achieving 1.5 volumes against resolved salt and was cooled at 0-5 0 C; 18.96 mL (0.13 moles) of trifluoroacetic anhydride (TFAA) were added to this salt, keeping the temperature for one hour at 0-5 0 C and allowing it to increase to room temperature until the end of the reaction. It was subsequently cooled again with water/ice and 53 mL of water were slowly added without surpassing 10 0 C. It was stirred and the phases were decanted; the organic phase was washed with 53 mL of water two times.
  • TFAA trifluoroacetic anhydride
  • the organic phase was diluted with 92 rriL of ethyl acetate (AcOEt) and 5.9 g ( 0.018 moles) of Na 2 WO 4 -2H 2 O and 3.0 mL of water were added and it was cooled to 0-5 0 C.
  • AcOEt ethyl acetate
  • a suspension with 1.0 Kg of (6S) -5, 6-dihydro-6-methyl-4H- thieno [2 , 3-b] thiopyran-4-one-7 , 7-dioxide was prepared in 15.76 L of methanol and was cooled at 0-5 0 C. Then, 52 g of NaBH 4 were added, in portions, without surpassing 10 0 C. Once the reaction has finished, 5.88 L of water were added. It was distilled at a reduced pressure to eliminate the methanol and the pH was adjusted to 6.5-7 with acetic acid. Then 25 L of CH 2 Cl 2 were added, it was stirred and the phases were separated. The aqueous phase was extracted with 6 L of CH 2 Cl 2 .

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  • Chemical & Material Sciences (AREA)
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Abstract

L’invention concerne un procédé d’obtention de cis-4-hydroxy-6-méthyl-5, 6-dihydro-4H-thiéno [2, 3-b] thiopyran-7,7-dioxyde, ses énantiomères ou leurs mélanges, par réduction de 5,6-dihydro-6-méthyl-4H-thiéno [2,3-b] thiopyran-4-one-7,7-dioxyde avec un agent réducteur qui génère des ions hydrure. Les composés obtenus sont utiles en tant qu’intermédiaires dans la synthèse d’ingrédients actifs chiraux.
PCT/EP2009/056496 2008-05-30 2009-05-28 Procédé d’obtention de 4-hydroxy-6-méthyl-5,6-dihydro-4h-thiéno [2,3-b] thiopyran-7,7-dioxyde et ses énantiomères, et ses applications Ceased WO2009144263A2 (fr)

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EP08380165A EP2128161A1 (fr) 2008-05-30 2008-05-30 Procédé d'obtention de 4-hydroxy-6-méthyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-7,7-dioxide et ses enantiomères, ainsi qu'applications correspondantes
EP08380165.4 2008-05-30

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WO2009144263A3 WO2009144263A3 (fr) 2010-01-14

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US4968814A (en) * 1990-04-18 1990-11-06 Merck & Co., Inc. (S)-Alkyl 3-(thien-2-ylthio)butyrate and analogs and synthesis thereof
DE69520354T2 (de) * 1994-12-28 2001-08-23 Kanegafuchi Kagaku Kogyo K.K., Osaka Verfahren zur herstellung eines carbonsäurederivates
ATE200283T1 (de) * 1994-12-28 2001-04-15 Kanegafuchi Chemical Ind Verfahren zur herstellung eines carbonsäurederivates
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US7109353B2 (en) * 2004-12-28 2006-09-19 Council Of Scientific And Industrial Research Process for preparing 5,6-dihydro-4-(S)-(ethylamino)-6-(S) methyl-4H-thieno[2,3b]thiopyran-2-sulphonamide-7,7-dioxide HCl

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